High Fat Diet versus Disturbed Blood Flow Conditions: Implications for Endothelial Glycocalyx Integrity and Pre‐Atherosclerotic Inflammation

Abstract

IntroductionEndothelial glycocalyx (GCX) shedding plays a role in endothelial dysfunction and increases vessel wall permeability to inflammatory cells contributing to atherogenesis. We sought to determine whether a high fat diet (HFD) or disturbed blood flow conditions, both well‐known atherogenic risk factors, would more detrimentally contribute to pre‐atherosclerotic loss of GCX integrity and vascular inflammation.Materials and MethodsC57BL/6‐background apolipoprotein E knockout (ApoE‐KO) mice were fed either a HFD or chow diet, and/or underwent a ligation of the left carotid artery (LCA), inducing disturbed flow conditions. After one week, mice were sacrificed and LCAs and right carotid arteries (RCAs) were preserved to compare GCX coverage and thickness and inflammatory macrophage accumulation in carotid arterial walls amongst and between cohorts.Results and DiscussionEndothelial GCX damage occurred in LCAs of HFD fed mice when compared to the control. More significant GCX damage occurred in the LCAs of mice exposed to disturbed flow by partial LCA ligation, also compared to control. Flow simulations conducted through SimVascular adequately characterized flow patterns, pressure, and wall shear stresses in non‐ligated vs. ligated mice. They confirmed the notion that the LCA partial ligation surgery does indeed reduce wall shear stress and increase pressure, characteristics of disturbed flow. No difference in macrophage accumulation in carotid arterial walls was observed when comparing the LCAs of control mice to the LCAs of HFD fed mice. However, macrophage infiltration in vessel walls showed a 20‐fold increase in LCAs exposed to disturbed flow following ligation, when compared to control LCAs.ConclusionsThis study was the first to demonstrate that disturbed flow contributes more detrimentally to pre‐atherosclerotic loss of GCX integrity and vascular inflammation. The study concluded that disturbed flow conditions induced by partial ligation, compared to HFD conditions, compromised the integrity of the endothelial GCX to a greater extent. We anticipate more rapid atherogenesis as a consequence of the severity of this flow induced GCX damage.Support or Funding InformationWe are pleased to acknowledge that this work was funded by the National Institute of Health (NIH) K01‐ HL125499 awarded to E Ebong, NIH R21‐DA042583 awarded to S Sridhar, and Air Force Office of Scientific Research (AFOSR) FA2386‐17‐1‐4042 awarded to S Sridhar.